DESCRIPTION: Hundreds of thousands of patients each year develop chronic pain and hyperalgesia. Many of these conditions remain poorly treated due to our limited understanding of functional organization in the spinal dorsal horn. Though extracellular studies in intact animals are well suited for defining the complex physiologic systems underlying pain signaling, intracellular studies in reduced preparations are best suited for determination of cellular processes. As a means to advance our understanding of spinal mechanisms of pain encoding we propose that these approaches should be combined. To this end we have adapted whole-cellpatch clamp intracellular recording for use in an intact anesthetized preparation of the rodent dorsal horn. Initial studies with this approach have already revealed new properties of neurons in the superficial spinal lamina. For example, biophysical parameters of spinal neurons were correlated to their profile of responses to peripheral stimuli. Additionally, a novel population of silent dorsal horn cells has been identified with latent responses to cutaneous stimuli that can be activated by membrane depolarization. Thus, in viva whole cell patch clamp in intact animals represents an exciting new approach for the study of cellular mechanisms of sensory integration in the dorsal horn. We propose here to extend our preliminary studies in cells of the superficial lamina, to expand the study to include neurons in deeper spinal lamina, and importantly, to determine the biophysical differences between projection and non-projection neurons. The studies outlined in this application will define the mechanisms by which the biophysical properties of cells influence both their action potential and subliminal excitatory and inhibitory responses to natural cutaneous stimuli. Additionally we will define the ionic bases of the biophysical differences among cells of differing functional classification. Knowledge of this kind is a key to advancing our knowledge of the cellular mechanisms of dorsal horn sensory integration and so will result in a better understanding and improved treatment of acute and chronic pain as well as further our understanding of conscious perception of somatic sensation.